Structural biology of chemokine receptors

chemokine receptors are g protein-coupled receptors that mediate migration and activation of leukocytes as an important part of a protective immune response to injury and infection. in addition, chemokine receptors are used by hiv-1 to infect cd4 positive cells. the structural bases of chemokine receptor recognition and signal transduction are currently being investigated. high-resolution x-ray diffraction and nmr spectroscopy of chemokines indicate that all these peptides exhibit a common folding pattern, in spite of its low degree of primary-sequence homology. chemokines' functional motifs have been identified by mutagenesis studies, and a possible mechanism for receptor recognition and activation is proposed, but high-resolution structure data of chemokine receptors is not yet available. studies with receptor chimeras have identified the putative extracellular domains as the major selectivity determinants. single-amino acid substitutions in the extracellular domains produce profound changes in receptor specificity, suggesting that motifs in these domains operate as a restrictive barrier to a common activation motif. similarly hiv-1 usage of chemokine receptors involves interaction of one or more extracellular domains of the receptor with conserved and variable domains on the viral envelope protein gp 120, indicating a highly complex interaction. elucidating the structural requirements for receptor interaction with chemokines and with hiv-1 will provide important insights into understanding the mechanisms of chemokine recognition and receptor activation. in addition, this information can greatly facilitate the design of effective inmunomodulatory and anti-hiv-1 therapeutic agents